Sapience Therapeutics, Inc. has announced the enrollment of the first patient in its Phase 2 dose expansion study evaluating ST316, a first-in-class antagonist of β-catenin, for the treatment of colorectal cancer (CRC). This follows the completion of the Phase 1 monotherapy dose escalation portion of the study in July 2024. The Phase 2 study, conducted across multiple sites in the United States, will assess ST316 in combination with relevant standards of care and in multiple lines of treatment for CRC patients.
Targeting Wnt/β-catenin Pathway in CRC
ST316 is designed to selectively shut down the Wnt/β-catenin signaling pathway in tumor cells while sparing normal cells, aiming to provide anti-cancer activity without the toxicities associated with broad inhibition of this pathway. The Wnt/β-catenin signaling pathway is highly active in several cancers, driving more than 80% of colorectal cancers. In the United States, over 1 million people are living with CRC, with approximately 150,000 new diagnoses expected this year alone.
Clinical Development and Rationale
The Phase 1-2 study (NCT05848739) is an open-label, dose-escalation and expansion study designed to determine the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and early efficacy of ST316. The Phase 1 portion tested various dose levels of ST316 in patients with advanced solid tumors known to harbor abnormalities of the Wnt/β-catenin signaling pathway, including CRC. The Phase 2 portion is now underway to further evaluate ST316 in CRC patients.
Dr. Abi Vainstein-Haras, Sapience's Chief Medical Officer, stated, "The promising results seen in our Phase 1 study demonstrate ST316's potential to be an effective therapy for Wnt pathway-driven cancers, including CRC among others. Given ST316's favorable safety and tolerability profile, together with robust pre-clinical data, Sapience is committed to maximizing the potential of ST316 in various therapeutic combinations across lines of treatment."
Mechanism of Action
ST316 is a peptide antagonist that disrupts the interaction between β-catenin and its co-activator, BCL9, a complex responsible for driving oncogene expression in cancers with aberrant Wnt/β-catenin pathway signaling. By preventing BCL9-driven nuclear localization of β-catenin, ST316 inhibits the formation of the Wnt enhanceosome protein complex, selectively suppressing the transcription of oncogenic Wnt target genes. This disruption affects genes that regulate proliferation, migration, invasion, and the metastatic potential of tumor cells, as well as genes that regulate immunosuppression of the tumor microenvironment. Preclinical models have shown that ST316 creates a pro-immune tumor microenvironment and is synergistic with checkpoint inhibition.
The Need for New CRC Treatments
"CRC patients who are refractory to current therapies desperately need new options like ST316," said Dr. Barry Kappel, Sapience's founder and Chief Executive Officer. "With CRC being the second-leading cause of cancer death in the United States, and with alarming increases in incidence among younger Americans, we are dedicated to widening the treatment options for this devastating disease."
